A Brief Narrative Review of the Underlying Mechanisms Whereby Omega-3 Fatty Acids May Influence Skeletal Muscle: From Cell Culture to Human Interventions.

Skeletal muscle is essential for human locomotion as well as maintaining metabolic homeostasis. Age-related reduction in skeletal muscle mass, strength, and function (i.e., sarcopenia) is a result of pathophysiological processes that include inflammation, alteration of molecular signaling for muscle protein synthesis and degradation, changes in insulin sensitivity, as well as altered skeletal muscle satellite cell activity. Finding strategies to mitigate skeletal muscle loss with age is deemed paramount as the percentage of the population continues to shift towards having more older adults with sarcopenia. Recent research indicates omega-3 fatty acid supplementation can influence anabolic or catabolic pathways in skeletal muscle. Our brief review will provide a synopsis of some underlying mechanisms that may be attributed to omega-3 fatty acid supplementation's effects on skeletal muscle. We will approach this review by focusing on cell culture, animal (pre-clinical models), and human studies evaluating omega-3 fatty acid supplementation, with suggestions for future research. In older adults, omega-3 fatty acids may possess some potential to modify pathophysiological pathways associated with sarcopenia; however, it is highly likely that omega-3 fatty acids need to be combined with other anabolic interventions to effectively ameliorate sarcopenia.

Omega-3 Fatty Acids for the Management of Osteoarthritis: A Narrative Review.

Osteoarthritis (OA) is a disease which results in degeneration of cartilage within joints and affects approximately 13.6% of adults over 20 years of age in Canada and the United States of America. OA is characterized by a state of low-grade inflammation which leads to a greater state of cellular catabolism disrupting the homeostasis of cartilage synthesis and degradation. Omega-3 polyunsaturated fatty acids (PUFAs) have been postulated as a potential therapeutic treatment option for individuals with OA. Omega-3 PUFAs are recognized for their anti-inflammatory properties, which could be beneficial in the context of OA to moderate pro-inflammatory markers and cartilage loss. The purpose of this narrative review is to outline recent pre-clinical and clinical evidence for the use of omega-3 in the management of OA.

Effects of Omega-3 Supplementation Alone and Combined with Resistance Exercise on Skeletal Muscle in Older Adults: A Systematic Review and Meta-Analysis.

Sarcopenia negatively affects skeletal muscle mass and function in older adults. Omega-3 (ω-3) fatty acid supplementation, with or without resistance exercise training (RET), is suggested to play a role as a therapeutic component to prevent or treat the negative effects of sarcopenia. A systematic review and meta-analysis were conducted on the impact of ω-3 fatty acid supplementation with or without RET on measures of muscle mass and function in older adults (≥55 y). The data sources included SPORTDiscus, PubMed, and Medline. All the study types involving ω-3 fatty acid supplementation on measures of muscle mass and function in older adults (without disease) were included. The mean differences (MDs) or standardized mean differences (SMDs) with 95% confidence intervals were calculated and pooled effects assessed. Sixteen studies (1660 females, 778 males) met our inclusion criteria and were included in the meta-analysis. ω-3 fatty acid supplementation did not impact lean tissue mass (SMD 0.09 [-0.10, 0.28]). Benefits were observed for lower body strength (SMD 0.54 [0.33, 0.75]), timed-up-and-go (MD 0.29 [0.23, 0.35]s), and 30-s sit-to-stand performance (MD 1.93 [1.59, 2.26] repetitions) but not walking performance (SMD -0.01 [-0.10, 0.07]) or upper body strength (SMD 0.05 [-0.04, 0.13]). Supplementing with ω-3 fatty acids may improve the lower-body strength and functionality in older adults.

Anti-Inflammatory and Anti-Catabolic Effects of Creatine Supplementation: A Brief Review.

It is well established that creatine supplementation, primarily when combined with resistance training, significantly increases measures of muscle mass and performance (primarily strength). Emerging research also indicates that creatine supplementation may have favorable effects on measures of bone biology. These anabolic adaptations may be related to creatine influencing cellular hydration status, high-energy phosphate metabolism, growth factors, muscle protein kinetics, and the bone remodeling process. Accumulating research also suggests that creatine supplementation has anti-inflammatory and anti-catabolic properties, which may help create a favorable environment for muscle and bone accretion and recovery from exercise. Creatine supplementation has the ability to decrease markers of inflammation and possibly attenuate cancerous tumor growth progression. From a musculoskeletal perspective, there is some evidence to show that creatine supplementation reduces measures of muscle protein catabolism (primarily in males) and bone resorption when combined with resistance training. The purpose of this brief review is to summarize the current body of literature examining the potential anti-inflammatory and anti-catabolic effects of creatine supplementation across various research populations.

Effects of Creatine Supplementation on Brain Function and Health.

While the vast majority of research involving creatine supplementation has focused on skeletal muscle, there is a small body of accumulating research that has focused on creatine and the brain. Preliminary studies indicate that creatine supplementation (and guanidinoacetic acid; GAA) has the ability to increase brain creatine content in humans. Furthermore, creatine has shown some promise for attenuating symptoms of concussion, mild traumatic brain injury and depression but its effect on neurodegenerative diseases appears to be lacking. The purpose of this narrative review is to summarize the current body of research pertaining to creatine supplementation on total creatine and phophorylcreatine (PCr) content, explore GAA as an alternative or adjunct to creatine supplementation on brain creatine uptake, assess the impact of creatine on cognition with a focus on sleep deprivation, discuss the effects of creatine supplementation on a variety of neurological and mental health conditions, and outline recent advances on creatine supplementation as a neuroprotective supplement following traumatic brain injury or concussion.

Variables Influencing the Effectiveness of Creatine Supplementation as a Therapeutic Intervention for Sarcopenia.

Sarcopenia is an age-related muscle condition characterized by a reduction in muscle quantity, force generating capacity and physical performance. Sarcopenia occurs in 8-13% of adults ≥ 60 years of age and can lead to disability, frailty, and various other diseases. Over the past few decades, several leading research groups have focused their efforts on developing strategies and recommendations for attenuating sarcopenia. One potential nutritional intervention for sarcopenia is creatine supplementation. However, research is inconsistent regarding the effectiveness of creatine on aging muscle. The purpose of this perspective paper is to: (1) propose possible reasons for the inconsistent responsiveness to creatine in aging adults, (2) discuss the potential mechanistic actions of creatine on muscle biology, (3) determine whether the timing of creatine supplementation influences aging muscle, (4) evaluate the evidence investigating the effects of creatine with other compounds (protein, conjugated linoleic acid) in aging adults, and (5) provide insight regarding the safety of creatine for aging adults.

Effectiveness of Creatine Supplementation on Aging Muscle and Bone: Focus on Falls Prevention and Inflammation.

Sarcopenia, defined as the age-related decrease in muscle mass, strength and physical performance, is associated with reduced bone mass and elevated low-grade inflammation. From a healthy aging perspective, interventions which overcome sarcopenia are clinically relevant. Accumulating evidence suggests that exogenous creatine supplementation has the potential to increase aging muscle mass, muscle performance, and decrease the risk of falls and possibly attenuate inflammation and loss of bone mineral. Therefore, the purpose of this review is to: (1) summarize the effects of creatine supplementation, with and without resistance training, in aging adults and discuss possible mechanisms of action, (2) examine the effects of creatine on bone biology and risk of falls, (3) evaluate the potential anti-inflammatory effects of creatine and (4) determine the safety of creatine supplementation in aging adults.

Omega-3 supplementation with resistance training does not improve body composition or lower biomarkers of inflammation more so than resistance training alone in older men.

The purpose of this study was to evaluate the effectiveness of 3.0 g/d of omega-3 fatty acid (eicosapentaenoic acid and docosahexaenoic acid) supplementation combined with progressive resistance training to improve body composition and lower inflammatory cytokines in older men when compared to placebo and resistance training. We hypothesized that completing a 12-week omega-3 supplementation period along with whole body resistance exercise (3 times/wk) would result in a significantly greater improvement in lean tissue mass as well as a significant decrease in interleukin-6 and tumor necrosis factor-α when compared to placebo. A total of 23 older men (≥65 years old) were randomized to an omega-3 supplementation group (n = 11) or placebo group (n = 12), and all the participants completed the same whole body progressive resistance training program. Baseline and 12-week data collection included body composition, muscle strength, functional ability, and inflammatory cytokines. Results indicated a significant main effect for time (all P < .05) for percent body fat (-2.5%), lean tissue mass (+1.1%), lumbar bone mineral density (+1.1%), hip bone mineral content (+1.1%), chest press strength (+31%), leg press strength (+37%), timed-up-and-go (-6.6%), and 6-minute walk distance (+4.5%) from baseline to post 12 weeks. No significant effects were noted for the 2 inflammatory cytokines measured (P > .05). We conclude that progressive resistance training exercise is an excellent method to enhance parameters of body composition, skeletal muscle strength, and functional ability in older men, whereas omega-3 supplementation did nothing to enhance these parameters or influence inflammatory biomarkers.

No effect of creatine monohydrate supplementation on inflammatory and cartilage degradation biomarkers in individuals with knee osteoarthritis.

The study purpose was to evaluate the effectiveness of creatine monohydrate supplementation (20 grams/day for 1 week and then 5 grams/day for 11 weeks) on inflammation (C-reactive protein, interleukin-1ß, interleukin-6, s100 A8/A9, and tumor necrosis factor-α) and cartilage degradation (serum cartilage oligomeric matrix protein) in patients with knee osteoarthritis. We hypothesized that supplementing with creatine monohydrate for 12 weeks would lower biomarkers of inflammation and cartilage degradation in patients with knee osteoarthritis when compared to placebo. A total of 18 patients with mild to moderate knee osteoarthritis were recruited and randomized in a double blind fashion to either a creatine supplementation group (N = 9) or a placebo (N = 9). At baseline and after 12 weeks of supplementation patients had inflammatory and cartilage degradation biomarkers measured in the systemic blood. Further, patients completed the Knee injury and Osteoarthritis Outcome (KOOS) questionnaire as well as had their isometric thigh strength evaluated using an isokinetic dynamometer at both time points. Results indicated that there was no difference between the creatine and placebo groups at 12 week follow up in the inflammatory biomarkers measured nor was there any difference between the groups for cartilage degradation (all P>.05). No statistical differences were noted for the KOOS questionnaire subscales or total score (all P>.05). Muscle strength testing indicated a main effect of time for both groups where isometric thigh strength at 0° of knee flexion was lowered significantly (P=.047). No other significant differences were found in the strength data. We conclude that 12 weeks of supplementation with creatine monohydrate does not affect inflammatory biomarkers, cartilage degradation, KOOS scores, or muscle strength in patients with mild to moderate knee osteoarthritis.

No evidence of hypoglycemia or hypotension in older adults during 6 months of flax lignan supplementation in a randomized controlled trial: a safety evaluation.

CONTEXT: The natural health product, BeneFlax, is a standardized flaxseed [Linum usitatissimum L. (Linaceae)] lignan enriched product with evidence of product quality and known quantity of the bioactive component, lignan. The acceptance of this natural health product for its various health benefits requires greater evidence of its safety in the general population. OBJECTIVE: We determined whether flaxseed lignan causes clinical hypoglycemia or hypotension in healthy older adults as an important aspect of safety. MATERIALS AND METHODS: Participants aged 49-87 years were randomized in a double-blind trial to receive flaxseed lignan (543 mg/day in BeneFlax) or placebo while completing a 6-month walking program. The 94 participants who completed the study were stratified by age (<65 years versus ≥65 years) and treatment category to determine whether older adults were more susceptible to adverse effects. RESULTS: After 6 months of treatment, average plasma glucose level (5.4 ± 0.6 mmol/L), systolic blood pressure (127 ± 14 mm Hg), and diastolic blood pressure (80 ± 9 mm Hg) were within normal clinical range. Controlling for sex and body mass index covariates resulted in no observed differences between plasma glucose or blood pressure measurements between treatment or age groups (p > 0.05). No incidents of hypoglycemia or hypotension were observed during BeneFlax treatment, suggesting that 543 mg falls at or below the no observable adverse effect level (NOAEL). DISCUSSION AND CONCLUSION: These data suggest the flaxseed lignan product BeneFlax does not pose a risk of hypoglycemia or hypotension in healthy adults aged 49-87 years.

Effect of nutritional interventions and resistance exercise on aging muscle mass and strength.

Sarcopenia, defined as the age-related loss of muscle mass, has a negative effect on strength, functional independence and overall quality of life. Sarcopenia is a multifactorial phenomenon characterized by changes in muscle morphology, protein and hormonal kinetics, oxidative stress, inflammation, physical activity and nutrition. It is well known that resistance exercise increases aging muscle mass and strength and these physiological adaptations from exercise may be further enhanced with certain nutritional interventions. Research indicates that essential amino acids and milk-based proteins, creatine monohydrate, essential fatty acids, and vitamin D may all have beneficial effects on aging muscle biology.

Conjugated linoleic acid combined with creatine monohydrate and whey protein supplementation during strength training.

PURPOSE: The authors examined the combined effects of conjugated linoleic acid (CLA), creatine (C), and whey protein (P) supplementation during strength training. METHODS: Sixty-nine participants (52 men, 17 women; M +/- SD age 22.5 +/-2.5 yr) were randomly assigned (double-blind) to 1 of 3 groups: CCP (6 g/d CLA + 9 g/d C + 36 g/d P; n = 22), CP (C + P + placebo oil; n = 25), or P (P + placebo oil; n = 22) during 5 wk of strength training (4-5 sets, 6-12 repetitions, 6 d/wk). Measurements were taken for body composition (air-displacement plethysmography), muscle thickness (ultrasound) of the flexors and extensors of the elbow and knee, 1-repetition-maximum (1-RM) strength (leg press and bench press), urinary markers of bone resorption (N-telopeptides, NTx), myofibrillar protein catabolism (3-methylhistidine; 3-MH), oxidative stress (8-isoprostanes), and kidney function (microalbumin) before and after training. RESULTS: Contrast analyses indicated that the CCP group had a greater increase in bench-press (16.2% +/- 11.3% vs. 9.7% +/- 17.0%; p < .05) and leg-press (13.1% +/- 9.9% vs. 7.7% +/-14.2%; p < .05) strength and lean-tissue mass (2.4% +/- 2.8% vs. 1.3% +/-4.1%; p < .05) than the other groups combined. All groups increased muscle thickness over time (p < .05). The relative change in 3-MH (CCP -4.7% +/- 70.2%, CP -0.4% +/- 81.4%, P 20.3% +/- 75.2%) was less in the groups receiving creatine (p < .05), with the difference for NTx also close to significance (p = .055; CCP -3.4% +/- 66.6%, CP -3.9% +/- 64.9%, P 26.0% +/- 63.8%). There were no changes in oxidative stress or kidney function. CONCLUSION: Combining C, CLA, and P was beneficial for increasing strength and lean-tissue mass during heavy resistance training.

A randomized controlled trial of the effects of flaxseed lignan complex on metabolic syndrome composite score and bone mineral in older adults.

A randomized double-blind placebo controlled study design was used to assess the effects of flaxseed lignan complex supplementation during exercise training on a metabolic syndrome composite score and osteoporosis risk in older adults. A total of 100 subjects (>or=50 years) were randomized to receive flaxseed lignan (543 mg.day-1 in a 4050 mg complex) or placebo while completing a 6 month walking program (30-60 min.day-1, 5-6 days.week-1). Fasting serum glucose, triacylglycerol (TAG), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, total cholesterol, interleukin-6, and tumor necrosis factor-alpha were measured every 2 months, while body composition, bone mineral density, and resting blood pressure were assessed at baseline and at 6 months. A composite Z score of 6 risk factors for metabolic syndrome (fasting glucose, HDL cholesterol, TAG, abdominal adiposity, blood pressure, and inflammatory cytokines) was calculated at baseline and at 6 months. Men taking placebo increased metabolic syndrome composite Z score (p < 0.05), but there were no changes in the other groups. A significant group x sex x time interaction was noted for TAG (p = 0.017) and diastolic blood pressure (p = 0.046), with men taking flaxseed lignan decreasing diastolic blood pressure relative to men taking placebo, and men taking placebo increasing TAG relative to men taking flax lignan. There were no differences between groups for change in bone measures, body composition, lipoproteins, or cytokines. Males taking the flaxseed lignan complex reduced metabolic syndrome score relative to men taking placebo, but a similar trend was not seen in females. Flaxseed lignan had no effect on bone mineral density or content, body composition, lipoproteins, glucose, or inflammation.

Alpha-linolenic acid supplementation and resistance training in older adults.

Increased inflammation with aging has been linked to sarcopenia. The purpose of this study was to evaluate the effects of supplementing older adults with alpha-linolenic acid (ALA) during a resistance training program, based on the hypothesis that ALA decreases the plasma concentration of the inflammatory cytokine tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, which in turn would improve muscle size and strength. Fifty-one older adults (65.4 +/- 0.8 years) were randomized to receive ALA in flax oil (~14 g.day-1) or placebo for 12 weeks while completing a resistance training program (3 days a week). Subjects were evaluated at baseline and after 12 weeks for muscle thickness of knee and elbow flexors and extensors (B-mode ultrasound), muscle strength (1 repetition maximum), body composition (dual energy X-ray absorptiometry), and concentrations of TNF-alpha and IL-6. Males supplementing with ALA decreased IL-6 concentration over the 12 weeks (62 +/- 36% decrease; p = 0.003), with no other changes in inflammatory cytokines. Chest and leg press strength, lean tissue mass, muscle thickness, hip bone mineral content and density, and total bone mineral content significantly increased, and percent fat and total body mass decreased with training (p < 0.05), with the only benefit of ALA being a significantly greater increase in knee flexor muscle thickness in males (p < 0.05). Total-body bone mineral density improved in the placebo group, with no change in the ALA group (p = 0.05). ALA supplementation lowers the IL-6 concentration in older men but not women, but had minimal effect on muscle mass and strength during resistance training.

Creatine, arginine alpha-ketoglutarate, amino acids, and medium-chain triglycerides and endurance and performance.

Creatine (Cr) supplementation increases muscle mass, strength, and power. Arginine a-ketoglutarate (A-AKG) is a precursor for nitric oxide production and has the potential to improve blood flow and nutrient delivery (i.e., Cr) to muscles. This study compared a commercial dietary supplement of Cr, A-AKG, glutamine, taurine, branched-chain amino acids, and medium-chain triglycerides with Cr alone or placebo on exercise performance and body composition. Thirty-five men (approximately 23 yr) were randomized to Cr + A-AKG (0.1 g . kg(-1) . d(-1) Cr + 0.075 g . kg(-1) . d(-1)A-AKG, n = 12), Cr (0.1 g . kg(-1) . d(-1), n = 11), or placebo (1 g . kg(-1) . d(-1) sucrose, n = 12) for 10 d. Body composition, muscle endurance (bench press), and peak and average power (Wingate tests) were measured before and after supplementation. Bench-press repetitions over 3 sets increased with Cr + A-AKG (30.9 +/- 6.6 +/- 34.9 +/- 8.7 reps; p < .01) and Cr (27.6 +/- 5.9 +/- 31.0 +/- 7.6 reps; p < .01), with no change for placebo (26.8 +/- 5.0 +/- 27.1 +/- 6.3 reps). Peak power significantly increased in Cr + A-AKG (741 +/- 112 +/- 794 +/- 92 W; p < .01), with no changes in Cr (722 +/- 138 +/- 730 +/- 144 W) and placebo (696 +/- 63 +/- 705 +/- 77 W). There were no differences in average power between groups over time. Only the Cr-only group increased total body mass (79.9 +/- 13.0 +/- 81.1 +/- 13.8 kg; p < .01), with no significant changes in lean-tissue or fat mass. These results suggest that Cr alone and in combination with A-AKG improves upper body muscle endurance, and Cr + A-AKG supplementation improves peak power output on repeated Wingate tests.

Low-dose creatine combined with protein during resistance training in older men.

PURPOSE: To determine whether low-dose creatine and protein supplementation during resistance training (RT; 3 d x wk(-1); 10 wk) in older men (59-77 yr) is effective for improving strength and muscle mass without producing potentially cytotoxic metabolites (formaldehyde). METHODS: Older men were randomized (double-blind) to receive 0.1 g x kg(-1) creatine + 0.3 g x kg(-1) protein (CP; n = 10), creatine (C; n = 13), or placebo (PLA; n = 12) on training days. Measurements before and after RT included lean tissue mass (air-displacement plethysmography), muscle thickness (ultrasound) of elbow, knee, and ankle flexors and extensors, leg and bench press strength, and urinary indicators of cytotoxicity (formaldehyde), myofibrillar protein degradation [3-methylhistidine (3-MH)],and bone resorption [cross-linked N-telopeptides of type I collagen (NTx)]. RESULTS: Subjects in C and CP groups combined experienced greater increases in body mass and total muscle thickness than PLA (P < 0.05). Subjects who received CP increased lean tissue mass (+5.6%) more than C (+2.2%) or PLA (+1.0%; P < 0.05) and increased bench press strength (+25%) to a greater extent than C and PLA combined (+12.5%; P < 0.05). CP and C did not differ from PLA for changes in formaldehyde production (+24% each). Subjects receiving creatine (C and CP) experienced a decrease in 3-MH by 40% compared with an increase of 29% for PLA (P < 0.05) and a reduction in NTx (-27%) versus PLA (+13%; P = 0.05). CONCLUSIONS: Low-dose creatine combined with protein supplementation increases lean tissue mass and results in a greater relative increase in bench press but not leg press strength. Low-dose creatine reduces muscle protein degradation and bone resorption without increasing formaldehyde production.

Effect of estrogenic compounds (estrogen or phytoestrogens) combined with exercise on bone and muscle mass in older individuals.

Exercise has a beneficial effect on bone, possibly by stimulating estrogen receptor alpha. Because estrogen up-regulates this receptor, estrogen therapy combined with exercise training may be optimal for increasing bone mineral density. Studies combining estrogen therapy and exercise training in postmenopausal women show mixed results, but indicate that the combination of interventions may be more effective for increasing bone mass than either intervention alone. Plant-like estrogens (i.e phytoestrogens such as soy isoflavones) may act as weak estrogen agonists or antagonists, have small beneficial effects on bone, and may interact with exercise for increasing bone mineral density. Phytoestrogen derived from flaxseed (flax lignans) has not been evaluated as extensively as soy isoflavones and thus its effect on bone is difficult to determine. Estrogen or soy isoflavones given to postmenopausal women results in a small increase in lean tissue mass that may be mediated through estrogen receptor alpha on muscle or through decreased inflammation.